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Vol. 62, Issue 2, 343-350, August 2002
-Aminobutyrate B
Receptor
Department of Molecular Pharmacology, Institute of Experimental
Medicine, Czech Academy of Science, Prague, Czech Republic (M.H.,
J.B.); Mécanismes Moléculaires des Communications
Cellulaires, Montpellier, France (M.H., L.P., B.D., J.-P.P.); and
Pharmacenter, University of Basel, Basel, Switzerland (B.B.)
The 
-aminobutyrate B (GABAB) receptor is the
first discovered G-protein-coupled receptor (GPCR) that needs two
subunits, GB1 and GB2, to form a functional receptor. The GB1
extracellular domain (ECD) binds GABA, and GB2 contains enough
molecular determinants for G-protein activation. The precise role of
the two subunits in G-protein coupling is investigated. GB1 and GB2 are
structurally related to the metabotropic glutamate,
Ca2+-sensing and other family 3 GPCRs in which the second
(i2) as well as the third (i3) intracellular loop play important roles in G-protein coupling. Here, the role of the i2 loops of GB1 and GB2 in
the GABAB receptor ability to activate G
-proteins is
investigated. To that aim, the i2 loops were swapped between GB1 and
GB2 heptahelical domains (HDs), either in the wild-type subunits or in
the chimeric subunits GB1/2 that contain the ECD of GB1 and the HD of
GB2. The effect of an additional mutation within the i3 loop of GB2 that prevents coupling of the heteromeric receptor was also examined. Combinations of interest were found to be correctly addressed at the
cell surface and to assemble into heteromers. Taken together our data
revealed the following new information on the G-protein coupling of the
heteromeric GABAB receptor: 1) the i2 loop of GB2 within
the GB2 HD is required for the heteromeric GABAB receptor to couple to G-proteins, whereas the i2 loop of GB1 is not; 2) the
presence of the i2 loop of GB2 within the GB1 HD is not sufficient to
allow coupling of GB1; 3) the GB2 HD activates the Gqi9 protein whether
it is associated with the GB2 or GB1 ECD; 4) in the combination with
two GB2 HDs, each is able to couple to G-proteins; and finally, 5) the
use of mutations in i2, i3, or both within the GB2 HD brings evidence
for the absence of domain swapping enabling the exchange of region
including i2 and i3 between the subunits.
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